Non-Mimetic Gels Direct Novel Crystallization Behavior of Lenalidomide [dataset]

Crystallization within supramolecular gels can yield distinct solid-state outcomes compared to conventional solution-phase methods, including the formation of novel crystal forms or selectively crystallizing one crystal form from a concomitant mixture. In several cases, tailoring the molecular structure of a gelator to mimic a pharmaceutical substrate has facilitated crystallization control, where non-mimetic gelators had no influence on the crystallization outcome compared to the solution phase. In this study, we investigate the crystallization behavior of lenalidomide within both mimetic and non-mimetic gels. Crystallization in a cyclopentanone gel using a non-mimetic gelator led to the discovery of a novel cyclopentanone hemi-solvate, inaccessible via solution-phase crystallization. Additionally, an ethanol gel of the same gelator promoted selective crystallization of the metastable Form 4 in ethanol, in contrast to the thermodynamically favored Form 1 obtained from solution. Gel-phase crystallization using a drug-mimetic gelator produced no deviation from the solution-phase polymorphic outcomes, in contrast to previously reported examples. Solution-state NMR studies showed no evidence of strong interactions between lenalidomide and either gelator, suggesting that the spatial arrangement of the non-mimetic gel fibers and/or possible confinement effects, rather than solution association, plays a critical role in directing crystallization behavior.